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The meaning of alignment: lessons from structural diversity.

Pirovano W, Feenstra KA, Heringa J - BMC Bioinformatics (2008)

Bottom Line: However, the available techniques do not fully consider the implications of protein structural diversity and typically generate a single alignment between sequences.We show that structural diversity has a significant effect on structural alignment.A comprehensive treatment of ambiguous alignment regions is crucial for further development of structural alignment applications and for the representation of alignments in general.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Integrative Bioinformatics VU (IBIVU), VU University Amsterdam, De Boelelaan 1081A, 1081HV Amsterdam, the Netherlands. pirovano@few.vu.nl

ABSTRACT

Background: Protein structural alignment provides a fundamental basis for deriving principles of functional and evolutionary relationships. It is routinely used for structural classification and functional characterization of proteins and for the construction of sequence alignment benchmarks. However, the available techniques do not fully consider the implications of protein structural diversity and typically generate a single alignment between sequences.

Results: We have taken alternative protein crystal structures and generated simulation snapshots to explicitly investigate the impact of structural changes on the alignments. We show that structural diversity has a significant effect on structural alignment. Moreover, we observe alignment inconsistencies even for modest spatial divergence, implying that the biological interpretation of alignments is less straightforward than commonly assumed. A salient example is the GroES 'mobile loop' where sub-Angstrom variations give rise to contradictory sequence alignments.

Conclusion: A comprehensive treatment of ambiguous alignment regions is crucial for further development of structural alignment applications and for the representation of alignments in general. For this purpose we have developed an on-line database containing our data and new ways of visualizing alignment inconsistencies, which can be found at http://www.ibi.vu.nl/databases/stralivari.

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Overview of the approach. SP scores are calculated to describe the differences at the sequence level between the reference and alternative structural alignments. In addition each alternative structure (either obtained with molecular simulation or from the PDB) is fit onto the reference structure and root mean square deviations (RMSDs) are calculated.
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Figure 2: Overview of the approach. SP scores are calculated to describe the differences at the sequence level between the reference and alternative structural alignments. In addition each alternative structure (either obtained with molecular simulation or from the PDB) is fit onto the reference structure and root mean square deviations (RMSDs) are calculated.

Mentions: To further elucidate the effect of structural diversity on structural alignment, we prepared two distinct comprehensive sets of alternative structures for proteins from the HOMSTRAD database of homologous protein families. The first set comprises proteins for which alternative crystal structures are available. The other set is derived from molecular dynamics simulations to explore a more extensive spectrum of possible structures. An overview of our analysis procedure is outlined in Figure 2.


The meaning of alignment: lessons from structural diversity.

Pirovano W, Feenstra KA, Heringa J - BMC Bioinformatics (2008)

Overview of the approach. SP scores are calculated to describe the differences at the sequence level between the reference and alternative structural alignments. In addition each alternative structure (either obtained with molecular simulation or from the PDB) is fit onto the reference structure and root mean square deviations (RMSDs) are calculated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2630330&req=5

Figure 2: Overview of the approach. SP scores are calculated to describe the differences at the sequence level between the reference and alternative structural alignments. In addition each alternative structure (either obtained with molecular simulation or from the PDB) is fit onto the reference structure and root mean square deviations (RMSDs) are calculated.
Mentions: To further elucidate the effect of structural diversity on structural alignment, we prepared two distinct comprehensive sets of alternative structures for proteins from the HOMSTRAD database of homologous protein families. The first set comprises proteins for which alternative crystal structures are available. The other set is derived from molecular dynamics simulations to explore a more extensive spectrum of possible structures. An overview of our analysis procedure is outlined in Figure 2.

Bottom Line: However, the available techniques do not fully consider the implications of protein structural diversity and typically generate a single alignment between sequences.We show that structural diversity has a significant effect on structural alignment.A comprehensive treatment of ambiguous alignment regions is crucial for further development of structural alignment applications and for the representation of alignments in general.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Integrative Bioinformatics VU (IBIVU), VU University Amsterdam, De Boelelaan 1081A, 1081HV Amsterdam, the Netherlands. pirovano@few.vu.nl

ABSTRACT

Background: Protein structural alignment provides a fundamental basis for deriving principles of functional and evolutionary relationships. It is routinely used for structural classification and functional characterization of proteins and for the construction of sequence alignment benchmarks. However, the available techniques do not fully consider the implications of protein structural diversity and typically generate a single alignment between sequences.

Results: We have taken alternative protein crystal structures and generated simulation snapshots to explicitly investigate the impact of structural changes on the alignments. We show that structural diversity has a significant effect on structural alignment. Moreover, we observe alignment inconsistencies even for modest spatial divergence, implying that the biological interpretation of alignments is less straightforward than commonly assumed. A salient example is the GroES 'mobile loop' where sub-Angstrom variations give rise to contradictory sequence alignments.

Conclusion: A comprehensive treatment of ambiguous alignment regions is crucial for further development of structural alignment applications and for the representation of alignments in general. For this purpose we have developed an on-line database containing our data and new ways of visualizing alignment inconsistencies, which can be found at http://www.ibi.vu.nl/databases/stralivari.

Show MeSH